EP0657423A1 - Aminosubstituted benzoylsulfonylurea and thiourea derivatives, process for their preparation and their use as pharmaceuticals - Google Patents

Aminosubstituted benzoylsulfonylurea and thiourea derivatives, process for their preparation and their use as pharmaceuticals Download PDF

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Publication number
EP0657423A1
EP0657423A1 EP94118931A EP94118931A EP0657423A1 EP 0657423 A1 EP0657423 A1 EP 0657423A1 EP 94118931 A EP94118931 A EP 94118931A EP 94118931 A EP94118931 A EP 94118931A EP 0657423 A1 EP0657423 A1 EP 0657423A1
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Prior art keywords
alkyl
formula
hydrogen
cycloalkyl
sulfur
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German (de)
French (fr)
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EP0657423B1 (en
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Heinrich Dr. Englert
Dieter Dr. Mania
Jens Dr. Hartung
Heinz Dr. Gögelein
Joachim Dr. Kaiser
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Hoechst AG
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Hoechst AG
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/58—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms
    • C07C335/42—Sulfonylthioureas; Sulfonylisothioureas

Definitions

  • alkyl describes straight-chain or branched, saturated hydrocarbon radicals.
  • the cycloalkyl radical can additionally carry alkyl substituents.
  • the elements fluorine, chlorine, bromine and iodine can be used as halogen substituents.
  • the carbon atoms of the alkyl side chain Y can be substituted asymmetrically.
  • the invention includes compounds of one or the other enantiomer and a racemic mixture or mixtures of the antipodes in different ratios. Furthermore, compounds with two to four centers of chirality can occur in the alkyl side chain Y. In this case, the invention includes both the individual antipodes themselves and a mixture of the enantiomers or diastereomers in different ratios, as well as the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers.
  • glibenclamide which is used therapeutically as an agent for the treatment of diabetes mellitus and in science as one widely regarded tool for the research of so-called ATP-sensitive potassium channels.
  • glibenclamide has other effects that have not yet been used therapeutically, but all of which are attributed to the blockage of these ATP-sensitive potassium channels. This includes in particular an antifibrillatory effect on the heart.
  • a simultaneous lowering of blood sugar would be undesirable or even dangerous, since it can further worsen the patient's condition.
  • Suitable experimental animals for the detection of such effects are, for example, mice, rats, guinea pigs, rabbits, dogs, monkeys or pigs.
  • the compounds I serve as active pharmaceutical ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the production of further active pharmaceutical ingredients.
  • the compounds I of the present invention are valuable medicaments for the treatment of cardiac arrhythmias of various origins and for the prevention of arrhythmically caused, sudden cardiac death and can therefore be used as antiarrhythmic agents.
  • arrhythmic disorders of the heart are supraventricular arrhythmias, such as atrial tachycardias, atrial flutter or paroxysmal supraventricular arrhythmias, or ventricular arrhythmias, such as ventricular extrasystoles, but especially life-threatening ventricular tachycardias or the particularly dangerous ventricular fibrillation.
  • arrhythmias are particularly suitable for cases in which arrhythmias are the result of a narrowing of a coronary vessel, such as occur, for example, in angina pectoris or during an acute heart attack or as a chronic consequence of a heart attack. They are therefore particularly suitable for post-infarct patients to prevent sudden cardiac death.
  • Other clinical pictures in which such rhythm disturbances and / or the sudden, arrhythmically related cardiac death play a role are, for example, heart failure or cardiac hypertrophy as a result of a chronically elevated blood pressure.
  • the compounds I can have a positive effect on reduced contractility of the heart.
  • This can be a disease-related decrease in heart contractility, for example in heart failure, but also acute cases such as heart failure due to shock.
  • the heart in the case of a heart transplant, the heart can resume its performance more quickly and reliably after the operation.
  • the compounds being used both for protecting the organs in the donor before and during removal, for protecting removed organs, for example during treatment with or their storage in physiological bath fluids , as with the transfer to the recipient organism can be used.
  • the compounds I and their physiologically acceptable salts are valuable therapeutic agents which can be used not only as antiarrhythmics, but also as prophylaxis in the event of cardiovascular disorders, heart failure, heart transplantation or cerebral vascular diseases in humans or Mammals (e.g. monkeys, dogs, mice, rats, rabbits, guinea pigs and cats) are suitable.
  • Physiologically acceptable salts of the compounds I are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14 to 18, compounds of the formula X, which can be prepared from non-toxic organic and inorganic bases and substituted benzenesulfonylureas I.
  • M (1) in the formula X are sodium, potassium, rubidium, calcium, magnesium, and the acid addition products of basic amino acids, such as lysine or arginine.
  • alkyl esters, halides (e.g. chlorides or bromides) or anhydrides of carboxylic acids of the formula are expediently suitable for the acylation of amino groups where R (7) is defined in Scheme 1 and U is a leaving group such as halide, (C1-C4) alkoxy, trihaloacetate, (C1-C4) carboxylate.
  • the amines XII acylated according to Scheme 1 can be prepared in a known manner be converted into the sulfonamides XIII.
  • the sulfonamides XIII are prepared by methods known per se and under reaction conditions which are known and suitable for the reactions mentioned. You can also make use of variants known per se, but not mentioned here in any more detail. If desired, the syntheses can be carried out in one, two or more steps.
  • acylated amine XII is converted into aromatic sulfonic acids and their derivatives such as sulfonic acid halides by electrophilic reagents in the presence or absence of inert solvents at temperatures from -10 to 120 ° C., preferably from 0 to 100 ° C. become.
  • sulfonic acids are the primary reaction products, they can be prepared either directly or by treatment with tertiary amines such as pyridine or trialkylamines or with alkali or alkaline earth metal hydroxides or reagents which form these basic compounds in situ, in a known manner by acid halides such as phosphorus trihalides , Phosphorus pentahalides, phosphorus oxychlorides, thionyl halides, oxalyl halides, are converted into sulfonic acid halides.
  • acid halides such as phosphorus trihalides , Phosphorus pentahalides, phosphorus oxychlorides, thionyl halides, oxalyl halides
  • the sulfonic acid derivatives are converted into sulfonamides in a manner known from the literature, preferably sulfonic acid chlorides are reacted in inert solvents at from 0 to 100 ° C. with aqueous ammonia.
  • the acyl protecting group of amine XIV can be removed with acids or bases.
  • the associated acid addition salt can be formed by cleavage with aqueous acids or acids in inert solvents.
  • aqueous acids or acids in inert solvents.
  • sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, polyphosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids are used example, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, phenylacetic acid, citric acid,
  • Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, or else alcoholates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methylate, sodium ethanolate, potassium methylate or potassium ethanolate, and reducing agents such as NaBH4 and other boranes or boranates.
  • the aromatic benzenesulfonamides of the formula II are prepared from the sulfonamide-substituted amines or their acid addition compounds prepared in this way.
  • R (1), R (2), R (3), R (4), R (5), R (6), E, X, Y and Z will be one or the other in individual cases other of the processes mentioned may be unsuitable for the preparation of the compounds I or at least make precautions to protect active groups necessary. Such cases can easily be recognized by the person skilled in the art, and in such cases it should not be difficult to use a different synthetic route successfully.
  • the compounds I can have one or more chiral centers. They can therefore be obtained in their preparation as racemates or, if optically active starting materials are used, also in optically active form. If the compounds have two or more chiral centers, they can be obtained in the synthesis as mixtures of racemates from which the individual isomers can be isolated in pure form, for example by recrystallization from inert solvents. Racemates obtained can, if desired, be separated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an optically active release agent.
  • Suitable release agents for basic compounds are, for example, optically active acids, such as the R or R, R and S or S, S forms of tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, camphorsulfonic acid, mandelic acid, malic acid or lactic acid.
  • Carbinols can also be amidated using chiral acylation reagents, for example R- or S- ⁇ -methylbenzyl isocyanate, and then separated.
  • the various forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a manner known per se. Enantiomer separations can also be achieved by chromatography on optically active carrier materials.
  • the compounds I according to the invention and their physiologically acceptable salts can be used for the production of pharmaceutical preparations.
  • they can be brought into a suitable dosage form together with at least one solid, liquid carrier or excipient, alone or in combination with other cardiovascular active medicaments, such as calcium antagonists, NO donors or ACE inhibitors.
  • cardiovascular active medicaments such as calcium antagonists, NO donors or ACE inhibitors.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, for example intravenous administration, or topical applications and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, Polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly.
  • Tablets, dragees, capsules, syrups, juices or drops are used in particular for oral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for rectal use, ointments, creams, pastes, lotions, gels, sprays for topical use , Foams, aerosols, solutions (for example in alcohols, such as ethanol or isopropanol, 1,2-propanediol or their mixtures with one another or with water) or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables.
  • Liposomal preparations containing stabilizers and / or wetting agents, emulsifiers, salts and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, salts for influencing the osmotic pressure, buffer substances, are also particularly suitable for topical use. Contain color and flavor and / or flavorings. If desired, they can also contain one or more further active ingredients, for example one or more vitamins.
  • the dosages necessary for the treatment of cardiac arrhythmias with the compounds I depend on whether acute or prophylactic is being treated.
  • a dose range of at least about 0.1 mg, preferably about 1 mg, in particular at least about 10 mg, to at most 100 mg, preferably at most 50 mg per kg and day is normally sufficient if prophylaxis is carried out.
  • a dose range of 1 to 10 mg per kg and day is very particularly preferred.
  • the dose can be divided as an oral or parenteral single dose into up to four individual doses. If acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration can be advantageous.
  • a preferred dose range in critical situations can then be 10 to 100 mg and can be administered, for example, as a continuous intravenous infusion.
  • reaction mixture is poured onto ice, filtered off with suction (melting point of the sulfonic acid chloride: 118 ° C.) and the precipitate is dissolved in acetone. Excess, concentrated, aqueous ammonia is added to this solution and, after the exothermic reaction has subsided, concentrated to a third of the original volume.
  • the 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2-fluorophenyl) ethyl] benzamide forms colorless crystals that melt at 203 ° C.
  • Action potential duration on the papillary muscle of the guinea pig (a) Introduction ATP deficiency states, such as those observed during ischemia in the heart muscle cell, lead to a shortening of the action potential duration. They are considered one of the causes of so-called reentryarrhythmias, which can cause sudden cardiac death. The opening of ATP-sensitive K channels by the decrease in ATP is considered to be the cause of this. (b) method Standard microelectrode technology is used to measure the action potential. For this purpose, guinea pigs of both sexes are killed by hitting the head, the hearts are removed, the papillary muscles are removed and hung up in an organ bath.
  • the organ bath is rinsed with Ringer's solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl2, 0.02% NaHCO3, and 0.1% glucose) and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36 ° C.
  • the muscle is stimulated via an electrode with rectangular pulses of 1 V and 1 ms duration and a frequency of 2 Hz.
  • the action potential is derived and registered by an intracellularly pierced glass microelectrode, which is filled with 3 mmol KCl solution.
  • the substances to be tested were added to the Ringer's solution in a concentration of 2.2 ⁇ 10 ⁇ 5 mol per liter.
  • the action potential is amplified on an oscilloscope using a Hugo Sachs amplifier shown.
  • the duration of the action potential is determined at a degree of repolarization of 95% (APD95).
  • Action potential reductions are either by adding a 1 ⁇ M solution of the potassium channel opener Rilmakalim (Hoe 234) [W. Linz, E. Klaus, U. Albus, RHA Becker, D. Mania, HC Englert, BA Schölkens Arzneistoffforschung / Drug Research, Volume 42 (II), 1992, pp. 1180 to 1185] or by adding 2-deoxyglucose (DEO ).
  • 2-deoxyglucose causes ATP deficiency states by blocking the glucose metabolism.
  • test substances were added to the bath solution as stock solutions in propanediol. The values given refer to measurements 30 minutes after the addition.
  • the APD95 is used as a control in the presence of DEO or Rilmakalim and in the absence of the test substance.
  • a fire-polished micropipette with an opening diameter of approximately 1 ⁇ m was placed on the cell using a micromanipulator.
  • a slight negative pressure in the patch pipette a high electrical seal was first created between the glass and the cell membrane and then the membrane spot under the measuring pipette was torn open by increasing the negative pressure.
  • the cell potential was registered with the aid of a patch clamp amplifier (L / M EPC 7) and the whole cell current was measured by applying a voltage ramp.
  • Stock solutions concentration 100 mmol) in dimethyl sulfoxide (DMSO) and corresponding dilutions in NaCl solution were prepared from the test substances. DMSO alone had no effect on the cell potential.

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Abstract

Amino-substituted benzenesulphonylureas and -thioureas of the formula I <IMAGE> are described. The compounds I are used for treating cardiac dysrhythmias and for preventing sudden heart death due to arrhythmias and can therefore be used as antiarrhythmics. They are particularly suitable for cases in which arrhythmias are the consequence of a constriction of a coronary vessel, such as in angina pectoris or acute myocardial infarct.

Description

Die Erfindung betrifft substituierte Benzolsulfonylharnstoffe und -thioharnstoffe I

Figure imgb0001

worin bedeuten:

R(1)
Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl;
r
null, 1, 2, 3, 4 oder 5;
p
1, 2, 3, 4, 5 oder 6;
R(2)
NR(3)R(4);
R(3) und R(4)
gemeinsam
eine (CH₂)₂₋₇-Kette, in der bei einer Kettenlänge von 4 bis 7 eine der CH₂-Gruppen durch Sauerstoff, Schwefel oder NR(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß;
oder
R(3), R(4), R(5)
unabhängig voneinander
Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl;
r
Null, 1, 2, 3, 4 oder 5;
p
1, 2, 3, 4, 5 oder 6;
E
Sauerstoff oder Schwefel;
Y
eine Kohlenwasserstoffkette der Formel -[CR(6)₂]n-; R(6) Wasserstoff oder (C₁-C₂)-Alkyl;
n
1, 2, 3 oder 4;
X
Wasserstoff, F, Cl, Br, I oder (C₁-C₆)-Alkyl;
Z
F, Cl, Br, I, NO₂, (C₁-C₄)-Alkoxy oder (C₁-C₄)-Alkyl.
The invention relates to substituted benzenesulfonylureas and thioureas I.
Figure imgb0001
in which mean:
R (1)
Hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆ ) Alkenyl;
r
zero, 1, 2, 3, 4 or 5;
p
1, 2, 3, 4, 5 or 6;
R (2)
NR (3) R (4);
R (3) and R (4)
together
a (CH₂) ₂₋₇ chain in which one of the CH₂ groups with a chain length of 4 to 7 can be replaced by oxygen, sulfur or NR (5), wherein between the N atom of the NR (3) R ( 4) and the oxygen, sulfur or NR (5) must be at least one CH₂ group;
or
R (3), R (4), R (5)
independently of each other
Hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆ ) Alkenyl;
r
Zero, 1, 2, 3, 4 or 5;
p
1, 2, 3, 4, 5 or 6;
E
Oxygen or sulfur;
Y
a hydrocarbon chain of the formula - [CR (6) ₂] n -; R (6) is hydrogen or (C₁-C₂) alkyl;
n
1, 2, 3 or 4;
X
Hydrogen, F, Cl, Br, I or (C₁-C₆) alkyl;
Z.
F, Cl, Br, I, NO₂, (C₁-C₄) alkoxy or (C₁-C₄) alkyl.

Der Begriff Alkyl beschreibt, sofern nicht anders angegeben, geradkettige` oder verzweigte, gesättigte Kohlenwasserstoffreste. Der Cycloalkylrest kann zusätzlich Alkylsubstituenten tragen.Unless otherwise stated, the term alkyl describes straight-chain or branched, saturated hydrocarbon radicals. The cycloalkyl radical can additionally carry alkyl substituents.

Als Halogensubstituenten sind die Elemente Fluor, Chlor, Brom und Iod einsetzbar. Die Kohlenstoffatome der Alkylseitenkette Y können asymmetrisch substituiert sein. Zur Erfindung gehören dabei Verbindungen des einen oder des anderen Enantiomers sowie einer racemischen Mischung oder Mischungen der Antipoden in unterschiedlichen Verhältnissen. Weiterhin können Verbindungen mit zwei bis vier Chiralitätszentren in der Alkylseitenkette Y auftreten. In diesem Fall gehören sowohl die einzelnen Antipoden für sich, als auch eine Mischung der Enantiomere oder Diastereomere in unterschiedlichen Verhältnissen, sowie die dazugehörigen Mesoverbindungen oder Mischungen aus Mesoverbindungen, den Enantiomeren oder Diastereomeren zur Erfindung.The elements fluorine, chlorine, bromine and iodine can be used as halogen substituents. The carbon atoms of the alkyl side chain Y can be substituted asymmetrically. The invention includes compounds of one or the other enantiomer and a racemic mixture or mixtures of the antipodes in different ratios. Furthermore, compounds with two to four centers of chirality can occur in the alkyl side chain Y. In this case, the invention includes both the individual antipodes themselves and a mixture of the enantiomers or diastereomers in different ratios, as well as the associated meso compounds or mixtures of meso compounds, the enantiomers or diastereomers.

Ähnliche Sulfonylharnstoffe sind aus der deutschen Offenlegungsschrift 2 413 514 und der deutschen Patentschrift 1 518 874 bekannt. Die DE-OS 2 413 514 beschreibt ausschließlich Blutzucker-konditionierende Stoffe mit p-Substitution in der zentralen Phenylgruppe. Hinweise auf Aminosubstituenten finden sich nicht.Similar sulfonylureas are known from German Offenlegungsschrift 2,413,514 and German Patent 1,518,874. DE-OS 2 413 514 describes only blood sugar conditioning substances with p-substitution in the central phenyl group. There are no indications of amino substituents.

In beiden Patent-Veröffentlichungen wird die blutzuckersenkende Wirkung der Sulfonylharnstoffe beschrieben. Als Prototyp solcher blutzuckersenkenden Sulfonylharnstoffe gilt das Glibenclamid, das als Mittel zur Behandlung des Diabetes mellitus therapeutisch verwendet wird und in der Wissenschaft als ein vielbeachtetes Werkzeug zur Erforschung sogenannter ATP sensitiver Kaliumkanäle dient. Neben seiner blutzuckersenkenden Wirkung besitzt das Glibenclamid noch andere Wirkungen, die bislang therapeutisch noch nicht eingesetzt werden können, die aber allesamt auf Blockade eben dieser ATP-sensitiven Kalium-Kanäle zurückgeführt werden. Dazu gehört insbesondere eine antifibrillatorische Wirkung am Herzen. Bei der Behandlung des Kammerflimmerns oder seiner Vorstufen wäre jedoch eine gleichzeitige Blutzuckersenkung unerwünscht oder gar gefährlich, da sie den Zustand des Patienten weiter verschlechtern kann.In both patent publications, the blood sugar-lowering effect of the sulfonylureas is described. The prototype of such blood sugar-lowering sulfonylureas is glibenclamide, which is used therapeutically as an agent for the treatment of diabetes mellitus and in science as one widely regarded tool for the research of so-called ATP-sensitive potassium channels. In addition to its hypoglycemic effect, glibenclamide has other effects that have not yet been used therapeutically, but all of which are attributed to the blockage of these ATP-sensitive potassium channels. This includes in particular an antifibrillatory effect on the heart. In the treatment of ventricular fibrillation or its precursors, a simultaneous lowering of blood sugar would be undesirable or even dangerous, since it can further worsen the patient's condition.

Aufgabe der vorliegenden Erfindung war es daher, Verbindungen zu synthetisieren, die eine gleich gute Herzwirkung wie Glibenclamid aufweisen, aber den Blutzucker in herzwirksamen Dosen oder Konzentrationen nicht oder deutlich geringer beeinflussen als Glibenclamid.It was therefore an object of the present invention to synthesize compounds which have an equally good cardiac action as glibenclamide, but which do not affect the blood sugar in cardiac effective doses or concentrations or do so significantly less than glibenclamide.

Als Versuchstiere zum Nachweis solcher Wirkungen eignen sich zum Beispiel Mäuse, Ratten, Meerschweinchen, Kaninchen, Hunde, Affen oder Schweine.Suitable experimental animals for the detection of such effects are, for example, mice, rats, guinea pigs, rabbits, dogs, monkeys or pigs.

Die Verbindungen I dienen als Arzneimittelwirkstoffe in der Human- und Veterinärmedizin. Ferner können sie als Zwischenprodukte zur Herstellung weiterer Arzneimittelwirkstoffe verwendet werden.The compounds I serve as active pharmaceutical ingredients in human and veterinary medicine. Furthermore, they can be used as intermediates for the production of further active pharmaceutical ingredients.

Bevorzugt sind die Verbindungen I, in denen bedeuten:

R(1)
Wasserstoff, (C₁-C₄)-Alkyl, CpF2p+1, (C₃-C₅)-Cycloalkyl, CH₂-(C₃-C₅)-Cycloalkyl oder (C₃-C₄)-Alkenyl;
p
1, 2 oder 3;
R(2)
NR(3)R(4);
R(3) und R(4)
gemeinsam
eine (CH₂)₂₋₇-Kette, in der bei einer Kettenlänge von 4 bis 7 eine der CH₂-Gruppen durch Sauerstoff, Schwefel oder NR(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß;
oder
R(3), R(4), R(5)
unabhängig voneinander
Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl;
r
Null, 1, 2, 3, 4 oder 5;
p
1, 2, 3, 4, 5 oder 6;
E
Sauerstoff oder Schwefel;
Y
eine Kohlenwasserstoffkette der Formel -[R(6)₂]n-; R(6) Wasserstoff oder (C₁-C₂)-Alkyl;
n
1, 2, 3 oder 4;
X
Wasserstoff, F, Cl oder (C₁-C₄)-Alkyl;
Z
Cl, F, (C₁-C₄)-Alkyl oder (C₁-C₄)-Alkoxy.
Preferred compounds I are those in which:
R (1)
Hydrogen, (C₁-C₄) alkyl, C p F 2p + 1 , (C₃-C₅) cycloalkyl, CH₂- (C₃-C₅) cycloalkyl or (C₃-C₄) alkenyl;
p
1, 2 or 3;
R (2)
NR (3) R (4);
R (3) and R (4)
together
a (CH₂) ₂₋₇ chain in which one of the CH₂ groups with a chain length of 4 to 7 can be replaced by oxygen, sulfur or NR (5), the between the N atom of NR (3) R (4) and the oxygen, sulfur or NR (5) must be at least one CH₂ group;
or
R (3), R (4), R (5)
independently of each other
Hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆ ) Alkenyl;
r
Zero, 1, 2, 3, 4 or 5;
p
1, 2, 3, 4, 5 or 6;
E
Oxygen or sulfur;
Y
a hydrocarbon chain of the formula - [R (6) ₂] n -; R (6) is hydrogen or (C₁-C₂) alkyl;
n
1, 2, 3 or 4;
X
Hydrogen, F, Cl or (C₁-C₄) alkyl;
Z.
Cl, F, (C₁-C₄) alkyl or (C₁-C₄) alkoxy.

Insbesondere sind die Verbindungen I bevorzugt, in denen bedeuten:

R(1)
Wasserstoff, (C₁-C₄)-Alkyl, (C₃-C₄)-Cycloalkyl oder (C₃-C₄)-Alkenyl;
R(2
) NR(3)R(4),
R(3) und R(4)
gemeinsam
eine (CH₂)₄₋₆ Kette, in der eine CH₂-Gruppe durch Sauerstoff, Schwefel oder N-R(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß,
oder
R(3) und R(4)
unabhängig voneinander
CH₃, C₂H₅, n-Propyl, iso-Propyl, cyclo-Propyl;
R(5)
Wasserstoff, CH₃ oder C₂H₅;
E
Sauerstoff oder Schwefel;
Y
eine Kohlenwasserstoffkette der Formel -[CR(6)₂]n-; R(6) Wasserstoff oder Methyl;
n
2 oder 3;
X
Wasserstoff, Cl, F oder (C₁-C₃)-Alkyl;
Z
F, Cl oder (C₁-C₃)-Alkoxy.
In particular, the compounds I are preferred in which:
R (1)
Hydrogen, (C₁-C₄) alkyl, (C₃-C₄) cycloalkyl or (C₃-C₄) alkenyl;
R (2nd
) NR (3) R (4),
R (3) and R (4)
together
a (CH₂) ₄₋₆ chain in which a CH₂ group can be replaced by oxygen, sulfur or NR (5), wherein between the N atom of the NR (3) R (4) and the oxygen, sulfur or NR (5) at least one CH₂ group must be present,
or
R (3) and R (4)
independently of each other
CH₃, C₂H₅, n-propyl, iso-propyl, cyclo-propyl;
R (5)
Hydrogen, CH₃ or C₂H₅;
E
Oxygen or sulfur;
Y
a hydrocarbon chain of the formula - [CR (6) ₂] n -; R (6) is hydrogen or methyl;
n
2 or 3;
X
Hydrogen, Cl, F or (C₁-C₃) alkyl;
Z.
F, Cl or (C₁-C₃) alkoxy.

Die Verbindungen I der vorliegenden Erfindung sind wertvolle Arzneimittel zur Behandlung von Herzrhythmusstörungen unterschiedlichster Genese und zur Verhinderung des arrhythmisch bedingten, plötzlichen Herztodes und können daher als Antiarrhythmika Verwendung finden. Beispiele arrhythmischer Störungen des Herzens sind supraventrikuläre Rhythmusstörungen, wie etwa Vorhof-Tachykardien, Vorhofflattern oder paroxysmale supraventrikuläre Rhythmusstörungen, oder ventrikuläre Rhythmusstörungen, wie ventrikuläre Extrasystolen, insbesondere aber lebensbedrohende ventrikuläre Tachykardien oder das besonders gefährliche Kammerflimmern. Sie eignen sich insbesondere für solche Fälle, in denen Arrhythmien Folge einer Verengung eines Koronargefäßes sind, wie sie beispielsweise bei Angina Pectoris oder während eines akuten Herzinfarkts oder als chronische Folge eines Herzinfarkts auftreten. Sie sind daher insbesondere bei Postinfarktpatienten zur Verhinderung des plötzlichen Herztodes geeignet. Weitere Krankheitsbilder, bei denen derartige Rhythmusstörungen und/oder der plötzliche, arrhythmisch bedingte Herztod eine Rolle spielen sind beispielsweise die Herzinsuffizienz oder die Herzhypertrophie als Folge eines chronisch erhöhten Blutdruckes.The compounds I of the present invention are valuable medicaments for the treatment of cardiac arrhythmias of various origins and for the prevention of arrhythmically caused, sudden cardiac death and can therefore be used as antiarrhythmic agents. Examples of arrhythmic disorders of the heart are supraventricular arrhythmias, such as atrial tachycardias, atrial flutter or paroxysmal supraventricular arrhythmias, or ventricular arrhythmias, such as ventricular extrasystoles, but especially life-threatening ventricular tachycardias or the particularly dangerous ventricular fibrillation. They are particularly suitable for cases in which arrhythmias are the result of a narrowing of a coronary vessel, such as occur, for example, in angina pectoris or during an acute heart attack or as a chronic consequence of a heart attack. They are therefore particularly suitable for post-infarct patients to prevent sudden cardiac death. Other clinical pictures in which such rhythm disturbances and / or the sudden, arrhythmically related cardiac death play a role are, for example, heart failure or cardiac hypertrophy as a result of a chronically elevated blood pressure.

Darüberhinaus können die Verbindungen I eine verminderte Kontraktilität des Herzens positiv beeinflussen. Hierbei kann es sich um ein krankheitsbedingtes Nachlassen der Herzkontraktilität handeln, beispielsweise bei Herzinsuffizienz, aber auch um akute Fälle wie Herzversagen bei Schockeinwirkungen. Ebenso kann bei einer Herztransplantation das Herz nach erfolgter Operation seine Leistungsfähigkeit rascher und zuverlässiger wieder aufnehmen. Gleiches gilt für Operationen am Herz, die eine vorübergehende Stillegung der Herzaktivität durch kardioplegische Lösungen erforderlich machen, wobei die Verbindungen sowohl für den Schutz der Organe im Spender vor und während der Entnahme, zum Schutz entnommener Organe beispielsweise bei Behandlung mit oder deren Lagerung in physiologischen Badflüssigkeiten, wie auch bei der Überführung in den Empfängerorganismus verwendet werden können.In addition, the compounds I can have a positive effect on reduced contractility of the heart. This can be a disease-related decrease in heart contractility, for example in heart failure, but also acute cases such as heart failure due to shock. Likewise, in the case of a heart transplant, the heart can resume its performance more quickly and reliably after the operation. The same applies to operations on the heart which necessitate a temporary cessation of cardiac activity by means of cardioplegic solutions, the compounds being used both for protecting the organs in the donor before and during removal, for protecting removed organs, for example during treatment with or their storage in physiological bath fluids , as with the transfer to the recipient organism can be used.

Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der Verbindungen I dadurch gekennzeichnet, daß man

  • (a) aromatische Sulfonamide der Formel II oder deren Salze der Formel III
    Figure imgb0002
mit einem R(1)-substituierten Isocyanat der Formel IV



        R(1) - N = C = O   IV



zu substituierten Benzolsulfonylharnstoffen I a umsetzt.The invention further relates to a process for the preparation of the compounds I, characterized in that
  • (a) aromatic sulfonamides of the formula II or their salts of the formula III
    Figure imgb0002
with an R (1) -substituted isocyanate of the formula IV



R (1) - N = C = O IV



converted to substituted benzenesulfonylureas I a.

Als Kationen M in den Salzen der Formel III kommen Alkali- und Erdalkaliionen in Betracht. Äquivalent zu den R(1)-substituierten Isocyanaten IV kann man R(1)-substituierte Carbamidsäureester, R(1)-substituierte Carbamidsäurehalogenide oder R(1)-substituierte Harnstoffe einsetzen.

  • (b) Unsubstituierte Benzolsulfonylharnstoffe I a [R(1) = H]
    Figure imgb0003
     kann man durch Umsetzungen aromatischer Benzolsulfonamide der Formel II oder deren Salze III mit Trialkylsilylisocyanat oder Siliciumtetraisocyanat und Hydrolyse der primären siliciumsubstituierten Benzolsulfonylharnstoffe herstellen. Weiterhin ist es möglich, Benzolsulfonamide II oder deren Salze III durch Umsetzung mit Halogencyanen und Hydrolyse der primär entstehenden N-Cyanosulfonamide mit Mineralsäuren bei Temperaturen zwischen 0 und 100°C darzustellen.
  • (c) Benzolsulfonylharnstoffe I a
    Figure imgb0004
     lassen sich aus aromatischen Benzolsulfonamiden II oder deren Salzen III und R(1)-substituierten Trichloracetamiden der Formel V
    Figure imgb0005
     in Gegenwart einer Base in einem inerten Lösungsmittel nach Synthesis 1987, 734 bis 735 bei Temperaturen von 25 bis 150°C darstellen.
    Als Basen eignen sich zum Beispiel Alkalimetall- oder Erdalkalimetallhydroxide, -hydride, -amide oder auch -alkoholate, wie Natriumhydroxid, Kaliumhydroxid, Calciumhydroxyd, Natriumhydrid, Kaliumhydrid, Calciumhydrid, Natriumamid, Kaliumamid, Natriummethylat, Natriumethanolat, Kaliummethylat oder Kaliumethanolat. Als inerte Lösungsmittel eignen sich Ether wie Tetrahydrofuran, Dioxan, Ethylenglykoldimethylether (Diglyme), Nitrile wie Acetonitril, Ester wie Ethylacetat, Carbonsäureamide wie Dimethylformamid (DMF) oder N-Methylpyrrolidon (NMP), Sulfoxide wie DMSO, Sulfone wie Sulfolan, Kohlenwasserstoffe wie Benzol, Toluol, Xylole. Weiterhin eignen sich auch Gemische dieser Lösungsmittel untereinander.
  • (d) Benzolsulfonylthioharnstoffe I b
    Figure imgb0006
     werden aus Benzolsulfonamiden II sowie deren Salze III und R(1)-substituierten Thioisocyanaten IV



            R(1) - N = C = S   IV



    dargestellt.
  • (e) Substituierte Benzolsulfonylharnstoffe der Formel I a können durch Umwandlungsreaktionen von Benzolsulfonylthioharnstoffen der Struktur I b dargestellt werden. Der Ersatz des Schwefelatoms durch ein Sauerstoffatom in den entsprechend substituierten Benzolsulfonylthioharnstoffen I b kann man beispielsweise mit Hilfe von Oxidationsmitteln wie Wasserstoffperoxid, Natriumperoxid oder Salpetersäure erreichen. Thioharnstoffe können auch durch Behandlung mit Phosgen oder Phosphorpentachlorid entschwefelt werden. Als Zwischenverbindungen werden Chlorameisensäureamidine bzw. Carbodiimide erhalten, die zum Beispiel durch Verseifung bzw. Anlagerung von Wasser in die entsprechenden substituierten Benzolsulfonylharnstoffe I a überführt werden. Isothioharnstoffe verhalten sich bei der Entschwefelung wie Thioharnstoffe und können demzufolge ebenso als Ausgangsstoffe für diese Reaktionen dienen.
  • (f) Benzolsulfonylharnstoffe I a lassen sich durch Umsetzungen von Aminen der Formel R(1)-NH₂ mit Benzolsulfonylisocyanaten der Formel VII
    Figure imgb0007
     herstellen. Ebenso können Amine R(1)-NH₂ mit
    Benzolsulfonylcarbamidsäureestern, -carbamidsäurehalogeniden oder Benzolsulfonylharnstoffen I a [mit R(1) = H] zu den Verbindungen I a umgesetzt werden.
  • (g) Benzolsulfonylthioharnstoffe I b lassen sich durch Umsetzungen von Aminen der Formel R(1)-NH₂ mit Benzolsulfonylisothiocyanaten der Formel VIII
    Figure imgb0008
     herstellen.
    Ebenso können Amine R(1)-NH₂ mit
    Benzolsulfonylcarbamidsäurethioestern, -carbamidsäurethiohalogeniden zu den Verbindungen I b umgesetzt werden.
As cations M in the salts of the formula III, alkali and alkaline earth metal ions can be used. Equivalent to the R (1) -substituted isocyanates IV, R (1) -substituted carbamic acid esters, R (1) -substituted carbamic acid halides or R (1) -substituted ureas can be used.
  • (b) Unsubstituted benzenesulfonylureas I a [R (1) = H]
    Figure imgb0003
     can by reactions of aromatic benzenesulfonamides of the formula II or their salts III with trialkylsilyl isocyanate or silicon tetraisocyanate and hydrolysis of the primary silicon-substituted Prepare benzenesulfonylureas. It is also possible to prepare benzenesulfonamides II or their salts III by reaction with cyanogen halides and hydrolysis of the primarily formed N-cyanosulfonamides with mineral acids at temperatures between 0 and 100.degree.
  • (c) Benzenesulfonylureas I a
    Figure imgb0004
     can be derived from aromatic benzenesulfonamides II or their salts III and R (1) -substituted trichloroacetamides of the formula V
    Figure imgb0005
     in the presence of a base in an inert solvent according to Synthesis 1987, 734 to 735 at temperatures of 25 to 150 ° C.
    Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or also alcoholates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium amide, potassium amide, sodium methylate, sodium ethanolate, potassium methylate or potassium ethanolate. Suitable inert solvents are ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (diglyme), nitriles such as acetonitrile, esters such as ethyl acetate, carboxamides such as dimethylformamide (DMF) or N-methylpyrrolidone (NMP), sulfoxides such as DMSO, sulfones such as sulfolane, Hydrocarbons such as benzene, toluene, xylenes. Mixtures of these solvents with one another are also suitable.
  • (d) benzenesulfonylthioureas I b
    Figure imgb0006
     are from benzenesulfonamides II and their salts III and R (1) -substituted thioisocyanates IV



    R (1) - N = C = S IV



    shown.
  • (e) Substituted benzenesulfonylureas of the formula I a can be prepared by conversion reactions of benzenesulfonylthioureas of the structure I b. The replacement of the sulfur atom by an oxygen atom in the appropriately substituted benzenesulfonylthioureas I b can be achieved, for example, with the aid of oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid. Thioureas can also be desulphurized by treatment with phosgene or phosphorus pentachloride. Chloroformic acid amidines or carbodiimides are obtained as intermediate compounds, which are converted into the corresponding substituted benzenesulfonylureas I a, for example by saponification or addition of water. During desulfurization, isothioureas behave like thioureas and can therefore also serve as starting materials for these reactions.
  • (f) Benzenesulfonylureas I a can be reacted with amines of the formula R (1) -NH₂ with benzenesulfonyl isocyanates of the formula VII
    Figure imgb0007
     produce. Likewise, amines R (1) -NH₂ with
    Benzenesulfonylcarbamic acid esters, carbamic acid halides or benzenesulfonylureas I a [with R (1) = H] are reacted to give the compounds I a.
  • (g) Benzenesulfonylthioureas I b can be reacted with amines of the formula R (1) -NH₂ with benzenesulfonyl isothiocyanates of the formula VIII
    Figure imgb0008
     produce.
    Likewise, amines R (1) -NH₂ with
    Benzenesulfonylcarbamidsäurethioestern, -carbamidsäurethiohalogeniden be converted to the compounds I b.

Die Verbindungen I sowie deren physiologisch unbedenkliche Salze sind wertvolle Therapeutika, die sich nicht nur als Antiarrhythmika, sondern auch als Prophylaxe bei Störungen des kardiovaskulären Systems, Herzinsuffizienz, Herztransplantation oder cerebralen Gefäßerkrankungen an Menschen oder Säugetieren (zum Beispiel Affen, Hunde, Mäuse, Ratten, Kaninchen, Meerschweinchen und Katzen) eignen.The compounds I and their physiologically acceptable salts are valuable therapeutic agents which can be used not only as antiarrhythmics, but also as prophylaxis in the event of cardiovascular disorders, heart failure, heart transplantation or cerebral vascular diseases in humans or Mammals (e.g. monkeys, dogs, mice, rats, rabbits, guinea pigs and cats) are suitable.

Unter physiologisch unbedenklichen Salzen der Verbindungen I versteht man nach Remmington's Pharmaceutical Science, 17. Auflage, 1985, Seiten 14 bis 18 Verbindungen der Formel X,

Figure imgb0009

die sich aus nicht toxischen organischen und anorganischen Basen und substituierten Benzolsulfonylharnstoffen I darstellen lassen.Physiologically acceptable salts of the compounds I are understood according to Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14 to 18, compounds of the formula X,
Figure imgb0009
which can be prepared from non-toxic organic and inorganic bases and substituted benzenesulfonylureas I.

Bevorzugt werden hierbei Salze, in denen M(1) in der Formel X Natrium-, Kalium, Rubidium, Calcium, Magnesium sind, sowie die Säureadditionsprodukte basischer Aminosäuren, wie zum Beispiel Lysin oder Arginin.Preferred are salts in which M (1) in the formula X are sodium, potassium, rubidium, calcium, magnesium, and the acid addition products of basic amino acids, such as lysine or arginine.

Die Ausgangsverbindungen für die erwähnten Syntheseverfahren der Benzolsulfonylharnstoffe I werden nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (zum Beispiel in den Standardwerken wie Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; sowie in den oben angegebenen Patentanmeldungen) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier aber nicht näher erwähnten Varianten Gebrauch machen. Die Ausgangsstoffe können gewünschtenfalls auch in situ gebildet werden, derart, daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter umsetzt.

Figure imgb0010

R(7)
CB₃,
B
Cl oder F;
O-(C₁-C₆)-Alkyl oder O-CH₂C₆H₅;
The starting compounds for the above-mentioned synthetic processes for the benzenesulfonylureas I are prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York; as well as in the patent applications cited above) under reaction conditions which are known and suitable for the reactions mentioned. It is also possible to use variants which are known per se but are not mentioned here in detail. If desired, the starting materials can also be formed in situ in such a way that they are not isolated from the reaction mixture but are immediately reacted further.
Figure imgb0010
R (7)
CB₃,
B
Cl or F;
O- (C₁-C₆) alkyl or O-CH₂C₆H₅;

So kann man Fluor-substituierte Phenylalkylamine nach Schema 1 acylieren. Zur Acylierung von Aminogruppen eignen sich zweckmäßig die Alkylester, Halogenide (z. B. Chloride oder Bromide) oder Anhydride von Carbonsäuren der Formel

Figure imgb0011

wobei R(7) in Schema 1 definiert ist und U eine Fluchtgruppe wie Halogenid, (C₁-C₄)-Alkoxy, Trihalogenacetat, (C₁-C₄)-Carboxylat ist.So you can acylate fluorine-substituted phenylalkylamines according to Scheme 1. The alkyl esters, halides (e.g. chlorides or bromides) or anhydrides of carboxylic acids of the formula are expediently suitable for the acylation of amino groups
Figure imgb0011
where R (7) is defined in Scheme 1 and U is a leaving group such as halide, (C₁-C₄) alkoxy, trihaloacetate, (C₁-C₄) carboxylate.

Die nach Schema 1 acylierten Amine XII können in bekannter Weise nach

Figure imgb0012

in die Sulfonamide XIII überführt werden. Die Sulfonamide XIII werden nach an sich bekannten Methoden hergestellt und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier aber nicht näher erwähnten Varianten Gebrauch machen. Die Synthesen können gewünschtenfalls in einem, zwei oder mehreren Schritten vollzogen werden. Insbesondere sind Verfahren bevorzugt, in denen das acylierte Amin XII durch elektrophile Reagenzien in An- oder Abwesenheit von inerten Lösungsmitteln bei Temperaturen von -10 bis 120°C, vorzugsweise von 0 bis 100°C in aromatische Sulfonsäuren sowie deren Derivate wie zum Beispiel Sulfonsäurehalogenide überführt werden. Beispielsweise können Sulfonierungen mit Schwefelsäure oder Oleum, Halogensulfonierungen mit Halogensulfonsäuren, Reaktionen mit Sulfurylhalogeniden in Gegenwart von wasserfreien Metallhalogeniden oder Thionylhalogeniden in Gegenwart von wasserfreien Metallhalogeniden mit anschließenden, in bekannter Weise durchgeführten Oxidationen zu aromatischen Sulfonsäurechloriden, durchgeführt werden. Sind Sulfonsäuren die primären Reaktionsprodukte, so können diese entweder direkt oder durch Behandlung mit tertiären Aminen, wie zum Beispiel Pyridin oder Trialkylaminen oder mit Alkali- oder Erdalkalihydroxiden oder Reagenzien, die diese basischen Verbindungen in situ bilden, in bekannter Weise durch Säurehalogenide wie zum Beispiel Phosphortrihalogenide, Phosphorpentahalogenide, Phosphoroxychloride, Thionylhalogenide, Oxalylhalogenide, in Sulfonsäurehalogenide überführt werden. Die Überführung der Sulfonsäurederivate in Sulfonamide erfolgt in literaturbekannter Weise, vorzugsweise werden Sulfonsäurechloride in inerten Lösungsmitteln bei Temperaturen von 0 bis 100°C mit wäßrigem Ammoniak umgesetzt.The amines XII acylated according to Scheme 1 can be prepared in a known manner
Figure imgb0012
be converted into the sulfonamides XIII. The sulfonamides XIII are prepared by methods known per se and under reaction conditions which are known and suitable for the reactions mentioned. You can also make use of variants known per se, but not mentioned here in any more detail. If desired, the syntheses can be carried out in one, two or more steps. In particular, processes are preferred in which the acylated amine XII is converted into aromatic sulfonic acids and their derivatives such as sulfonic acid halides by electrophilic reagents in the presence or absence of inert solvents at temperatures from -10 to 120 ° C., preferably from 0 to 100 ° C. become. For example, sulfonations with sulfuric acid or oleum, halogen sulfonations with halogen sulfonic acids, reactions with sulfuryl halides in the presence of anhydrous metal halides or thionyl halides in the presence of anhydrous metal halides with subsequent, in a known manner, oxidation to aromatic sulfonic acid chlorides can be carried out. If sulfonic acids are the primary reaction products, they can be prepared either directly or by treatment with tertiary amines such as pyridine or trialkylamines or with alkali or alkaline earth metal hydroxides or reagents which form these basic compounds in situ, in a known manner by acid halides such as phosphorus trihalides , Phosphorus pentahalides, phosphorus oxychlorides, thionyl halides, oxalyl halides, are converted into sulfonic acid halides. The sulfonic acid derivatives are converted into sulfonamides in a manner known from the literature, preferably sulfonic acid chlorides are reacted in inert solvents at from 0 to 100 ° C. with aqueous ammonia.

Die Sulfonamide XIII werden nach Schema 3 mit Aminen der Formel HNR(3)R(4) bei Temperaturen von 25 bis 160°C in An- oder Abwesenheit inerter Lösungsmittel zu den aminosubstituierten Sulfonamiden XIV umgesetzt.

Figure imgb0013
According to Scheme 3, the sulfonamides XIII are reacted with amines of the formula HNR (3) R (4) at temperatures from 25 to 160 ° C. in the presence or absence of inert solvents to give the amino-substituted sulfonamides XIV.
Figure imgb0013

Die Acyl-Schutzgruppe des Amins XIV läßt sich mit Säuren oder Basen abspalten. Durch Spaltung mit wäßrigen Säuren oder Säuren in inerten Lösungsmitteln kann das zugehörige Säureadditionssalz entstehen. Für diese Umsetzung kommen zum Beispiel Schwefelsäure, Halogenwasserstoffsäuren, wie Chlorwasserstoffsäure oder Bromwasserstoffsäure, Phosphorsäuren wie Orthophosphorsäure, Polyphosphorsäure, Sulfaminsäure, ferner organische Säuren, insbesondere aliphatische, alicyclische, araliphatische, aromatische oder heterocyclische ein- oder mehrbasige Carbon-, Sulfon- oder Schwefelsäuren, zum Beispiel Essigsäure, Propionsäure, Pivalinsäure, Diethylessigsäure, Malonsäure, Bernsteinsäure, Pimelinsäure, Fumarsäure, Maleinsäure, Milchsäure, Weinsäure, Äpfelsäure, Benzoesäure, Salicylsäure, 2- oder 3-Phenylpropionsäure, Phenylessigsäure, Citronensäure, Gluconsäure, Ascorbinsäure, Nicotinsäure, Isonicotinsäure, Methan- oder Ethansulfonsäure, Ethandisulfonsäure, 2-Hydroxyethansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, Napthalin-mono- und disulfonsäuren, Laurylschwefelsäure in Betracht.The acyl protecting group of amine XIV can be removed with acids or bases. The associated acid addition salt can be formed by cleavage with aqueous acids or acids in inert solvents. For this reaction, for example, sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, polyphosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, are used example, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, phenylacetic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, laurylsulfuric acid.

Die basische Spaltung des acylierten Amins der Formel XIV kann in wäßrigen oder inerten Lösungsmitteln erfolgen. Als Basen eignen sich zum Beispiel Alkalimetall- oder Erdalkalimetallhydroxide, oder auch -alkoholate, wie Natriumhydroxid, Kaliumhydroxid, Calciumhydroxyd, Natriummethylat, Natriumethanolat, Kaliummethylat oder Kaliumethanolat, sowie Reduktionsmittel wie NaBH₄ und andere Borane bzw. Boranate.The basic cleavage of the acylated amine of the formula XIV can be carried out in aqueous or inert solvents. Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, or else alcoholates, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methylate, sodium ethanolate, potassium methylate or potassium ethanolate, and reducing agents such as NaBH₄ and other boranes or boranates.

Aus den so hergestellten sulfonamidsubstituierten Aminen oder deren Säureadditionsverbindungen werden, wie oben erwähnt, die aromatischen Benzolsulfonamide der Formel II hergestellt. Je nach der Natur der Glieder R(1), R(2), R(3), R(4), R(5), R(6), E, X, Y und Z wird in einzelnen Fällen das eine oder andere der genannten Verfahren für die Herstellung der Verbindungen I ungeeignet sein oder zumindest Vorkehrungen zum Schutz aktiver Gruppen notwendig machen. Derartige Fälle können vom Fachmann unschwer erkannt werden, und es sollte in solchen Fällen keine Schwierigkeiten bereiten, einen anderen Syntheseweg erfolgreich anzuwenden.As mentioned above, the aromatic benzenesulfonamides of the formula II are prepared from the sulfonamide-substituted amines or their acid addition compounds prepared in this way. Depending on the nature of the terms R (1), R (2), R (3), R (4), R (5), R (6), E, X, Y and Z will be one or the other in individual cases other of the processes mentioned may be unsuitable for the preparation of the compounds I or at least make precautions to protect active groups necessary. Such cases can easily be recognized by the person skilled in the art, and in such cases it should not be difficult to use a different synthetic route successfully.

Die Verbindungen I können ein oder mehrere chirale Zentren besitzen. Sie können daher bei ihrer Herstellung als Racemate oder, falls optisch aktive Ausgangsstoffe verwendet werden, auch in optisch aktiver Form erhalten werden. Weisen die Verbindungen zwei oder mehr chirale Zentren auf, dann können sie bei der Synthese als Gemische von Racematen anfallen, aus denen man die einzelnen Isomere, beispielsweise durch Umkristallisieren aus inerten Lösungsmitteln, in reiner Form isolieren kann. Erhaltene Racemate können, falls erwünscht, nach an sich bekannten Methoden mechanisch oder chemisch in ihre Enantiomeren getrennt werden. So können aus dem Racemat durch Umsetzung mit einem optisch aktiven Trennmittel Diastereomere gebildet werden. Als Trennmittel für basische Verbindungen eignen sich zum Beispiel optisch aktive Säuren, wie die R- bzw. R,R- und S- bzw. S,S-Formen von Weinsäure, Dibenzoylweinsäure, Diacetylweinsäure, Camphersulfonsäure, Mandelsäure, Äpfelsäure oder Milchsäure. Carbinole können ferner mit Hilfe chiraler Acylierungsreagenzien, zum Beispiel R- oder S-α-Methylbenzylisocyanat amidiert und dann getrennt werden. Die verschiedenen Formen der Diastereomeren können in an sich bekannter Weise, zum Beispiel durch fraktionierte Kristallisation, getrennt und die Enantiomeren der Formel I können in an sich bekannter Weise aus den Diastereomeren in Freiheit gesetzt werden. Enantiomerentrennungen gelingen ferner durch Chromatographie an optischaktiven Trägermaterialien.The compounds I can have one or more chiral centers. They can therefore be obtained in their preparation as racemates or, if optically active starting materials are used, also in optically active form. If the compounds have two or more chiral centers, they can be obtained in the synthesis as mixtures of racemates from which the individual isomers can be isolated in pure form, for example by recrystallization from inert solvents. Racemates obtained can, if desired, be separated mechanically or chemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an optically active release agent. Suitable release agents for basic compounds are, for example, optically active acids, such as the R or R, R and S or S, S forms of tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, camphorsulfonic acid, mandelic acid, malic acid or lactic acid. Carbinols can also be amidated using chiral acylation reagents, for example R- or S-α-methylbenzyl isocyanate, and then separated. The various forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a manner known per se. Enantiomer separations can also be achieved by chromatography on optically active carrier materials.

Die erfindungsgemäßen Verbindungen I und ihre physiologisch unbedenklichen Salze können zur Herstellung pharmazeutischer Zubereitungen verwendet werden. Hierbei können sie zusammen mit mindestens einem festen, flüssigen Träger oder Hilfsstoff allein oder in Kombination mit anderen Herz-Kreislaufaktiven Arzneimitteln, wie etwa Calcium-Antagonisten, NO-Donatoren oder ACE-Hemmern in eine geeignete Dosierungsform gebracht werden. Diese Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin verwendet werden. Als Trägerstoffe kommen organische oder anorganische Substanzen in Frage, die sich für die enterale (zum Beispiel orale), parenterale, wie zum Beispiel die intravenöse Applikation, oder topische Anwendungen eignen und mit den neuen Verbindungen nicht reagieren, beispielsweise Wasser, pflanzliche Öle, Benzylalkohole, Polyethylenglykole, Glycerintricacetat, Gelatine, Kohlenhydrate, wie Lactose oder Stärke, Magnesiumstearat, Talk, Lanolin, Vaseline. Zur oralen Anwendung dienen insbesondere Tabletten, Dragees, Kapseln, Sirupe, Säfte oder Tropfen, zur rektalen Anwendung Lösungen, vorzugsweise ölige oder wäßrige Lösungen, ferner Suspensionen, Emulsionen oder Implantate, für die topische Anwendung Salben, Cremes, Pasten, Lotionen, Gele, Sprays, Schäume, Aerosole, Lösungen (zum Beispiel in Alkoholen, wie Ethanol oder Isopropanol, 1,2-Propandiol oder deren Gemische untereinander oder mit Wasser) oder Puder. Die neuen Verbindungen können auch lyophilisiert und die erhaltenen Lyophilisate zum Beispiel zur Herstellung von Injektionspräparaten verwendet werden. Insbesondere für die topische Anwendung kommen auch liposomale Zubereitungen in Betracht, die Stabilisierungs- und/oder Netzmittel, Emulgatoren, Salze und/oder Hilfsstoffe wie Gleit-, Konservierungs-, Stabilisierungs- und/oder Netzmittel, Salze zur Beeinflussung des osmotischen Druckes, Puffersubstanzen, Farb- und Geschmacks- und/ oder Aromastoffe enthalten. Sie können, falls erwünscht, auch einen oder mehrere weitere Wirkstoffe enthalten, zum Beispiel ein oder mehrere Vitamine.The compounds I according to the invention and their physiologically acceptable salts can be used for the production of pharmaceutical preparations. Here, they can be brought into a suitable dosage form together with at least one solid, liquid carrier or excipient, alone or in combination with other cardiovascular active medicaments, such as calcium antagonists, NO donors or ACE inhibitors. These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, for example intravenous administration, or topical applications and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, Polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petroleum jelly. Tablets, dragees, capsules, syrups, juices or drops are used in particular for oral use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for rectal use, ointments, creams, pastes, lotions, gels, sprays for topical use , Foams, aerosols, solutions (for example in alcohols, such as ethanol or isopropanol, 1,2-propanediol or their mixtures with one another or with water) or powder. The new compounds can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injectables. Liposomal preparations containing stabilizers and / or wetting agents, emulsifiers, salts and / or auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, salts for influencing the osmotic pressure, buffer substances, are also particularly suitable for topical use. Contain color and flavor and / or flavorings. If desired, they can also contain one or more further active ingredients, for example one or more vitamins.

Die Dosierungen, die zur Behandlung von Herzrhythmusstörungen mit den Verbindungen I notwendig sind, hängen davon ab, ob akut oder prophylaktisch therapiert wird. Normalerweise kommt man mit einem Dosisbereich von mindestens etwa 0.1 mg, vorzugsweise etwa 1 mg, insbesondere mindestens etwa 10 mg, bis höchstens 100 mg, vorzugsweise höchstens 50 mg pro kg und Tag aus, wenn Prophylaxe betrieben wird. Ganz besonders bevorzugt ist ein Dosisbereich von 1 bis 10 mg pro kg und Tag. Die Dosis kann dabei als orale oder parenterale Einzeldosis in bis zu vier Einzeldosen aufgeteilt werden. Werden akute Fälle von Herzrhythmusstörungen behandelt, beispielsweise auf einer Intensivstation, kann die parenterale Verabreichung vorteilhaft sein. Ein bevorzugter Dosisbereich in kritischen Situationen kann dann 10 bis 100 mg betragen und beispielsweise als intravenöse Dauerinfusion verabreicht werden.The dosages necessary for the treatment of cardiac arrhythmias with the compounds I depend on whether acute or prophylactic is being treated. A dose range of at least about 0.1 mg, preferably about 1 mg, in particular at least about 10 mg, to at most 100 mg, preferably at most 50 mg per kg and day is normally sufficient if prophylaxis is carried out. A dose range of 1 to 10 mg per kg and day is very particularly preferred. The dose can be divided as an oral or parenteral single dose into up to four individual doses. If acute cases of cardiac arrhythmias are treated, for example in an intensive care unit, parenteral administration can be advantageous. A preferred dose range in critical situations can then be 10 to 100 mg and can be administered, for example, as a continuous intravenous infusion.

Erfindungsgemäß können außer den in den Ausführungsbeispielen beschriebenen Verbindungen die in der folgenden Tabelle zusammengestellten Verbindungen I erhalten werden:

  • (1) 2-Methoxy-5-fluor-N-{5-[-1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(4-morpholino)-phenyl]-ethyl}-benzamid,
  • (2) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(4-morpholino)-phenyl]-ethyl}-benzamid,
  • (3) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(4-morpholino)-phenyl]-(3-propyl)}-benzamid,
  • (4) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(4-thiomorpholino)-phenyl]-ethyl}-benzamid,
  • (5) 2-Methoxy-5-fluor-N-{5-[-1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(4-thiomorpholino)-phenyl]-ethyl}-benzamid,
  • (6) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(4-thiomorpholino)-phenyl]-ethyl}-benzamid,
  • (7) 2-Methoxy-5-fluor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(4-N-methylpiperazyl)-phenyl]-ethyl}-benzamid,
  • (8) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(4-N-methylpiperazyl)-phenyl]-ethyl}-benzamid,
  • (9) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(N,N-dimethylamino)-phenyl]-ethyl}-benzamid,
  • (10) 2-Methoxy-5-fluor-N-{5-[-1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(N,N-dimethylamino)-phenyl]-ethyl}-benzamid,
  • (11) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(N,N-diethylamino)-phenyl]-ethyl}-benzamid,
  • (12) 2-Methoxy-5-chlor-N-{5-[-1-sulfonylamino-N-(methylaminocarbonyl)-2-(1-pyrrolidyl)-phenyl]-ethyl}-benzamid.
    Figure imgb0014
In addition to the compounds described in the exemplary embodiments, the compounds I listed in the following table can be obtained according to the invention:
  • (1) 2-methoxy-5-fluoro-N- {5 - [- 1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (4-morpholino) phenyl] ethyl} benzamide,
  • (2) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (4-morpholino) phenyl] ethyl} benzamide,
  • (3) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (4-morpholino) phenyl] - (3-propyl)} - benzamide,
  • (4) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (4-thiomorpholino) phenyl] ethyl} benzamide,
  • (5) 2-methoxy-5-fluoro-N- {5 - [- 1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (4-thiomorpholino) phenyl] ethyl} benzamide,
  • (6) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (4-thiomorpholino) phenyl] ethyl} benzamide,
  • (7) 2-methoxy-5-fluoro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (4-N-methylpiperazyl) phenyl] ethyl} benzamide,
  • (8) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (4-N-methylpiperazyl) phenyl] ethyl} benzamide,
  • (9) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (N, N-dimethylamino) phenyl] ethyl} benzamide,
  • (10) 2-methoxy-5-fluoro-N- {5 - [- 1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (N, N-dimethylamino) phenyl] ethyl} benzamide,
  • (11) 2-methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (N, N-diethylamino) phenyl] ethyl} benzamide,
  • (12) 2-Methoxy-5-chloro-N- {5 - [- 1-sulfonylamino-N- (methylaminocarbonyl) -2- (1-pyrrolidyl) phenyl] ethyl} benzamide.
    Figure imgb0014

Beispiel 1:Example 1:

2-Methoxy-5-chlor-N-{5-[1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(4-morpholino)-phenyl]-ethyl}-benzamid.

Figure imgb0015

0.45 g (1.0 mmol) 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-(4-morpholino)-phenyl)-ethyl]-benzamid werden unter Argon in 5 ml trockenem DMF gelöst und bei 0°C mit 42 mg Natriumhydrid (60 %ige Dispersion in Weißöl) versetzt. Das Kältebad wird entfernt und die Reaktionsmischung 30 Minuten bei Raumtemperatur nachgerührt. In die Lösung des Natriumsulfonamids trägt man 0.10 g Methylisothiocyanat ein und rührt 5 Stunden bei Raumtemperatur sowie 1 Stunde bei 70°C nach. Nach dem Abkühlen gießt man die Reaktionsmischung auf 50 ml 0.5N Salzsäure. Das ausgefallene Produkt wird abgesaugt und getrocknet. Ausbeute: 96 %, Schmp.: 195 bis 196°C.2-methoxy-5-chloro-N- {5- [1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (4-morpholino) phenyl] ethyl} benzamide.
Figure imgb0015
0.45 g (1.0 mmol) of 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2- (4-morpholino) phenyl) ethyl] benzamide are dissolved in 5 ml of dry DMF under argon and at 0 ° C with 42 mg sodium hydride (60% dispersion in white oil). The The cold bath is removed and the reaction mixture is stirred at room temperature for 30 minutes. 0.10 g of methyl isothiocyanate is introduced into the solution of sodium sulfonamide and the mixture is stirred for 5 hours at room temperature and for 1 hour at 70 ° C. After cooling, the reaction mixture is poured onto 50 ml of 0.5N hydrochloric acid. The precipitated product is suctioned off and dried. Yield: 96%, mp: 195 to 196 ° C.

Herstellung der Ausgangsverbindung:Preparation of the starting compound:

1.39 g (10.0 mmol) 4-Fluor-β-phenylethylamin werden in 40 ml Pyridin gelöst, mit einer Spatelspitze Dimethylaminopyridin versetzt und mit einer Lösung von 2.15 g (10.5 mmol) 2-Methoxy-5-chlorbenzoylchlorid versetzt. Die Reaktionsmischung wird auf kalte verdünnte Salzsäure gegossen, das ausgefallene Produkt abgesaugt und getrocknet. Man erhält 4-Fluor-β-phenylethyl-(2-methoxy-5-chlorbenzamid) als farblose Kristalle vom Schmelzpunkt 85°C. Das so erhaltene Benzamid wird in kalte Chlorsulfonsäure eingetragen. Nach vollständiger Umsetzung gießt man die Reaktionsmischung auf Eis, saugt ab (Schmelzpunkt des Sulfonsäurechlorids: 118°C) und löst den Niederschlag in Aceton. Diese Lösung wird mit überschüssigem, konzentriertem, wäßrigem Ammoniak versetzt und nach Abklingen der exothermen Reaktion auf ein Drittel des ursprünglichen Volumens eingeengt. Das 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-fluorphenyl)-ethyl]-benzamid bildet farblose Kristalle, die bei 203°C schmelzen. Dreistündiges Erhitzen von 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-fluorphenyl)-ethyl]-benzamid in überschüssigem Morpholin unter Rückfluß liefert 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-(4-morpholino)-phenyl)-ethyl]-benzamid, das durch Säulenchromatographie (Kieselgel 60, Heptan/Ethylacetat Gradient von 2:1 nach 4:1) isoliert wird. Das Produkt schmilzt bei 236°C.1.39 g (10.0 mmol) of 4-fluoro-β-phenylethylamine are dissolved in 40 ml of pyridine, a spatula tip of dimethylaminopyridine is added and a solution of 2.15 g (10.5 mmol) of 2-methoxy-5-chlorobenzoyl chloride is added. The reaction mixture is poured onto cold, dilute hydrochloric acid, and the precipitated product is filtered off with suction and dried. 4-Fluoro-β-phenylethyl- (2-methoxy-5-chlorobenzamide) is obtained as colorless crystals with a melting point of 85 ° C. The benzamide thus obtained is introduced into cold chlorosulfonic acid. After the reaction is complete, the reaction mixture is poured onto ice, filtered off with suction (melting point of the sulfonic acid chloride: 118 ° C.) and the precipitate is dissolved in acetone. Excess, concentrated, aqueous ammonia is added to this solution and, after the exothermic reaction has subsided, concentrated to a third of the original volume. The 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2-fluorophenyl) ethyl] benzamide forms colorless crystals that melt at 203 ° C. Heating 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2-fluorophenyl) ethyl] benzamide in excess morpholine under reflux for three hours gives 2-methoxy-5-chloro-N- [5- ( 1-sulfonylamino-2- (4-morpholino) phenyl) ethyl] benzamide, which is isolated by column chromatography (silica gel 60, heptane / ethyl acetate gradient from 2: 1 to 4: 1). The product melts at 236 ° C.

Beispiel 2:Example 2:

2-Methoxy-5-chlor-N-{5-[1-sulfonylamino-N-(methylaminothiocarbonyl)-2-(1-piperidyl)-phenyl]-ethyl}-benzamid.

Figure imgb0016

0.45 g (1.0 mmol) 2-Methoxy-4-chlor-N-[5-(1-sulfonylamino-2-(1-piperidyl)-phenyl)-ethyl]-benzamid werden unter Argon in 5 ml trockenem DMF gelöst und bei 0°C mit 42 mg Natriumhydrid (60 %ige Dispersion in Weißöl) versetzt. Das Kältebad wird entfernt und die Reaktionsmischung 30 Minuten bei Raumtemperatur nachgerührt. Zur Lösung des Natriumsulfonamids fügt man 0.10 g Methylisothiocyanat und rührt 5 Stunden bei Raumtemperatur sowie 1 Stunde bei 70°C nach. Nach dem Abkühlen auf 50 ml 0.5N Salzsäure gegossen. Das ausgefallene Produkt wird abgesaugt und getrocknet. Ausbeute: 95 %, Schmp.: 90°C.2-methoxy-5-chloro-N- {5- [1-sulfonylamino-N- (methylaminothiocarbonyl) -2- (1-piperidyl) phenyl] ethyl} benzamide.
Figure imgb0016
0.45 g (1.0 mmol) of 2-methoxy-4-chloro-N- [5- (1-sulfonylamino-2- (1-piperidyl) phenyl) ethyl] benzamide are dissolved in 5 ml of dry DMF under argon and at 0 ° C with 42 mg sodium hydride (60% dispersion in white oil). The cold bath is removed and the reaction mixture is stirred at room temperature for 30 minutes. 0.10 g of methyl isothiocyanate are added to the solution of the sodium sulfonamide and the mixture is stirred for 5 hours at room temperature and for 1 hour at 70 ° C. After cooling to 50 ml of 0.5N hydrochloric acid poured. The precipitated product is suctioned off and dried. Yield: 95%, mp: 90 ° C.

Herstellung der Ausgangsverbindung:Preparation of the starting compound:

Eine Lösung von 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-fluorphenyl)-ethyl]-benzamid in überschüssigem Piperidin wird 4 Stunden unter Rückfluß erhitzt. Nach Abdestillieren des Lösungsmittels im Vakuum läßt sich 2-Methoxy-5-chlor-N-[5-(1-sulfonylamino-2-(1-piperidyl)-phenyl)-ethyl]-benzamid säulenchromatographisch (Kieselgel 60, Heptan/Ethylacetat Gradient von 2:1 nach 4:1) als farblose Kristalle vom Schmelzpunkt 225°C isolieren.A solution of 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2-fluorophenyl) ethyl] benzamide in excess piperidine is heated under reflux for 4 hours. After the solvent has been distilled off in vacuo, 2-methoxy-5-chloro-N- [5- (1-sulfonylamino-2- (1-piperidyl) phenyl) ethyl] benzamide can be column chromatographed (silica gel 60, heptane / ethyl acetate gradient from 2: 1 to 4: 1) isolate as colorless crystals with a melting point of 225 ° C.

Pharmakologische Daten:Pharmacological data:

Mit den folgenden Modellen können die therapeutischen Eigenschaften der Verbindungen I nachgewiesen werden:
(1) Aktionspotentialdauer am Papillarmuskel des Meerschweinchens:
(a) Einleitung
ATP-Mangelzustände, wie sie während einer Ischämie in der Herzmuskelzelle beobachtet werden, führen zu einer Verkürzung der Aktionspotentialdauer. Sie gelten als eine der Ursachen für sogenannte Reentryarrhythmien, die den plötzlichen Herztod verursachen können. Die Öffnung von ATP-sensitiven K-Kanälen durch das Absinken von ATP gilt hierfür als ursächlich.
(b) Methode
Zur Messung des Aktionspotentials wird eine Standard-Mikroelektroden-Technik eingesetzt. Hierfür werden Meerschweinchen beiderlei Geschlechts durch Schlag auf den Kopf getötet, die Herzen entnommen, die Papillarmuskeln herausgetrennt und in einem Organbad aufgehängt. Das Organbad wird mit Ringerlösung (0.9 % NaCl, 0.048 % KCl, 0.024 % CaCl₂, 0.02 % NaHCO₃, und 0.1 % Glucose) durchspült und mit einer Mischung aus 95 % Sauerstoff und 5 % Kohlendioxid bei einer Temperatur von 36°C begast. Der Muskel wird über eine Elektrode mit Rechteck-Impulsen von 1 V und 1 ms Dauer und einer Frequenz von 2 Hz angeregt. Das Aktionspotential wird durch eine intrazellulär eingestochene Glas-Mikroelektrode, die mit 3 mMol KCl-Lösung gefüllt ist, abgeleitet und registriert. Die zu prüfenden Substanzen wurden der Ringerlösung in einer Konzentration von 2.2·10⁻⁵ Mol pro Liter zugesetzt. Das Aktionspotential wird mit einem Amplifier von Hugo Sachs verstärkt auf einem Oszilloskop dargestellt. Die Dauer des Aktionspotentials wird bei einem Repolarisierungsgrad von 95 % (APD₉₅) bestimmt. Aktionspotentialverkürzungen werden entweder durch Zugabe einer 1 µM starken Lösung des Kaliumkanalöffners Rilmakalim (Hoe 234) [W. Linz, E. Klaus, U. Albus, R.H.A. Becker, D. Mania, H. C. Englert, B. A. Schölkens Arzneimittelforschung/Drug Research, Band 42 (II), 1992, S. 1180 bis 1185] oder durch Zugabe von 2-Desoxyglucose (DEO) hervorgerufen. Durch 2-Desoxyglucose werden in der experimentellen Physiologie ATP-Mangelzustände durch Blockade des Glucosestoffwechsels hervorgerufen. Der aktionspotential-verkürzende Effekt dieser Substanzen wurde durch die gleichzeitige Gabe der Testsubstanzen verhindert oder veringert. Testsubstanzen wurden als Stammlösungen in Propandiol der Badlösung zugesetzt. Die angegebenen Werte beziehen sich auf Messungen 30 Minuten nach der Zugabe. Als Kontrolle gilt die APD₉₅ in Gegenwart von DEO oder Rilmakalim und in Abwesenheit der Testsubstanz.
(c) Resultate:
Folgende Werte wurden gemessen: Messung APD₉₅-DEOa ) [ms] APD₉₅-Rilmakalima ) [ms] Kontrolle < 40 < 40 Beispiel 1 110 (172) n = 1 121 ± 14 (150 ± 9) n = 3 Beispiel 2 105 ± 11 (141 ± 4) n = 3 153 ± 15 (158 ± 12) n = 3 a) den Meßwerten aus n-Versuchen sind die korrespondierenden Leerwerte in Klammern nachgestellt. Die Leerwerte sind die APD₉₅-Werte zu Versuchsbeginn ohne DEO, Rilmakalim und Testsubstanz in der Ringerlösung.
(2) Membranpotential an isolierten β-Zellen:
(a) Einleitung
Der Wirkmechanismus der blutzuckersenkenden Sulfonylharnstoffe ist in groben Zügen aufgeklärt. Zielorgan sind die β-Zellen des Pankreas wo es zu einer Mehrausschüttung des blutzuckersenkenden Hormons Insulin kommt. Die Freisetzung von Insulin wird über das Zellmembranpotential gesteuert. Glibenclamid bewirkt eine Depolarisation der Zellmembran, was über einen vermehrten Einstrom von Calciumionen die Insulinfreisetzung fördert. Das Ausmaß dieser Depolarisation der Zellmembran ΔU wurde an RINm5F Zellen, einer Pankreastumorzellinie, für einige der erfindungsgemäßen Verbindungen bestimmt. Die Wirkstärke einer Verbindung in diesem Modell sagt das Ausmaß des blutzuckersenkenden Potentials dieser Verbindung voraus.
(b) Methode
Zellkultur von RINm5F Zellen
RINm5F Zellen wurden in RPMI 1640 Kulturmedium (Flow), dem 11 mmol Glukose, 10 % (vol/vol) fötales Kälberserum, 2 mmol Glutamin und 50 µg/ml Gentamycin zugesetzt wurde, bei 37°C kultiviert. Für die Untersuchungen wurden die Zellen durch Inkubation (ca. 3 Minuten) in einem Ca²⁺-freien Medium, das 0.25 % Trypsin enthielt, isoliert und auf Eis aufbewahrt.
Meßmethode
Isolierte RINm5F Zellen wurden in eine Plexiglaskammer auf einem inversen Mikroskop, das mit Differential-Interferenz-Kontrast Optik ausgerüstet ist, gebracht. Unter optischer Kontrolle (400-fache Vergrößerung) wurde eine feuerpolierte Mikropipette mit Öffnungsdurchmessser von etwa 1 µm mit Hilfe eines Mikromanipulators auf die Zelle aufgesetzt. Durch Anlegen eines leichten Unterdruckes in der Patch-Pipette wurde zunächst eine hohe elektrische Abdichtung zwischen Glas und Zellmembran hergestellt und anschließend durch Erhöhung des Unterdruckes der Membranfleck unter der Meßpipette aufgerissen. In dieser Ganzzellenkonfiguration wurde mit Hilfe eines Patch-Clamp Verstärkers (L/M EPC 7) das Zellpotential registriert und durch Anlegen einer Spannungsrampe der Ganzzellenstrom gemessen.
Lösungen: Die Patch-Pipette war mit KCl-Lösung gefüllt (in mmol): 140 KCl, 10 NaCl, 1.1 MgCl₂, 0.5 EGTA, 1 Mg-ATP, 10 HEPES, pH = 7.2, und im Bad befand sich NaCl-Lösung (in mmol): 140 NaCl, 4.7 KCl, 1.1 MgCl₂, 2 CaCl₂, 10 HEPES, pH = 7.4. Von den Testsubstanzen wurden Stocklösungen (Konzentration 100 mmol) in Dimethylsulfoxid (DMSO) und entsprechende Verdünnungen in NaCl-Lösung hergestellt. DMSO alleine hatte keinen Effekt auf das Zellpotential. Um das Zellpotential unter Kontrollbedingungen zu stabilisieren, wurde der Öffner für ATP-sensitive K⁺ Kanäle Diazoxid (100 µmol) bei allen Versuchen in die Badlösung zugegeben. Alle Experimente wurden bei 34 ± 1 °C durchgeführt.
(c) Ergebnisse (Die Konzentrationen der erfindungsgemäßen Verbindungen betragen in den Versuchen 10⁻⁶ Mol pro Liter) Messung ΔU (mv)a ) Beispiel 1 14 (-76) n = 7 Beispiel 2 19 (-76) n = 3 a) den Meßwerten aus n-Versuchen sind die korrespondierenden Leerwerte in Klammern nachgestellt. Die Leerwerte sind die Zellpotentiale unter Diazoxid-Gabe. The therapeutic properties of the compounds I can be demonstrated with the following models:
(1) Action potential duration on the papillary muscle of the guinea pig:
(a) Introduction
ATP deficiency states, such as those observed during ischemia in the heart muscle cell, lead to a shortening of the action potential duration. They are considered one of the causes of so-called reentryarrhythmias, which can cause sudden cardiac death. The opening of ATP-sensitive K channels by the decrease in ATP is considered to be the cause of this.
(b) method
Standard microelectrode technology is used to measure the action potential. For this purpose, guinea pigs of both sexes are killed by hitting the head, the hearts are removed, the papillary muscles are removed and hung up in an organ bath. The organ bath is rinsed with Ringer's solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl₂, 0.02% NaHCO₃, and 0.1% glucose) and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a temperature of 36 ° C. The muscle is stimulated via an electrode with rectangular pulses of 1 V and 1 ms duration and a frequency of 2 Hz. The action potential is derived and registered by an intracellularly pierced glass microelectrode, which is filled with 3 mmol KCl solution. The substances to be tested were added to the Ringer's solution in a concentration of 2.2 · 10⁻⁵ mol per liter. The action potential is amplified on an oscilloscope using a Hugo Sachs amplifier shown. The duration of the action potential is determined at a degree of repolarization of 95% (APD₉₅). Action potential reductions are either by adding a 1 µM solution of the potassium channel opener Rilmakalim (Hoe 234) [W. Linz, E. Klaus, U. Albus, RHA Becker, D. Mania, HC Englert, BA Schölkens Arzneimittelforschung / Drug Research, Volume 42 (II), 1992, pp. 1180 to 1185] or by adding 2-deoxyglucose (DEO ). In experimental physiology, 2-deoxyglucose causes ATP deficiency states by blocking the glucose metabolism. The action potential shortening effect of these substances was prevented or reduced by the simultaneous administration of the test substances. Test substances were added to the bath solution as stock solutions in propanediol. The values given refer to measurements 30 minutes after the addition. The APD₉₅ is used as a control in the presence of DEO or Rilmakalim and in the absence of the test substance.
(c) Results:
The following values were measured: Measurement APD₉₅-DEO a ) [ms] APD₉₅-Rilmakalim a ) [ms] control <40 <40 example 1 110 (172) n = 1 121 ± 14 (150 ± 9) n = 3 Example 2 105 ± 11 (141 ± 4) n = 3 153 ± 15 (158 ± 12) n = 3 a) the measured values from n tests are followed by the corresponding blank values in brackets. The blank values are the APD₉₅ values at the start of the test without DEO, Rilmakalim and test substance in the Ringer solution.
(2) Membrane potential on isolated β cells:
(a) Introduction
The mechanism of action of the blood sugar-lowering sulfonylureas has been broadly elucidated. The target organ is the β-cells of the pancreas, where there is an increased release of the blood sugar-lowering hormone insulin. The release of insulin is controlled via the cell membrane potential. Glibenclamide causes a depolarization of the cell membrane, which promotes insulin release through an increased influx of calcium ions. The extent of this depolarization of the cell membrane ΔU was determined on RINm5F cells, a pancreatic tumor cell line, for some of the compounds according to the invention. The potency of a compound in this model predicts the extent of the compound's hypoglycemic potential.
(b) method
Cell culture of RINm5F cells
RINm5F cells were cultured in RPMI 1640 culture medium (flow) to which 11 mmol glucose, 10% (vol / vol) fetal calf serum, 2 mmol glutamine and 50 µg / ml gentamycin were added at 37 ° C. For the investigations, the cells were isolated by incubation (about 3 minutes) in a Ca²⁺-free medium containing 0.25% trypsin and kept on ice.
Measurement method
Isolated RINm5F cells were placed in a plexiglass chamber on an inverted microscope equipped with differential interference contrast optics. Under optical control (400x magnification), a fire-polished micropipette with an opening diameter of approximately 1 µm was placed on the cell using a micromanipulator. By applying a slight negative pressure in the patch pipette, a high electrical seal was first created between the glass and the cell membrane and then the membrane spot under the measuring pipette was torn open by increasing the negative pressure. In this whole cell configuration, the cell potential was registered with the aid of a patch clamp amplifier (L / M EPC 7) and the whole cell current was measured by applying a voltage ramp.
Solutions: The patch pipette was filled with KCl solution (in mmol): 140 KCl, 10 NaCl, 1.1 MgCl₂, 0.5 EGTA, 1 Mg-ATP, 10 HEPES, pH = 7.2, and there was NaCl solution in the bath ( in mmol): 140 NaCl, 4.7 KCl, 1.1 MgCl₂, 2 CaCl₂, 10 HEPES, pH = 7.4. Stock solutions (concentration 100 mmol) in dimethyl sulfoxide (DMSO) and corresponding dilutions in NaCl solution were prepared from the test substances. DMSO alone had no effect on the cell potential. In order to stabilize the cell potential under control conditions, the opener for ATP-sensitive K⁺ channels diazoxide (100 µmol) was added to the bath solution in all experiments. All experiments were carried out at 34 ± 1 ° C.
(c) Results (The concentrations of the compounds according to the invention are 10⁻⁶ mol per liter in the tests) Measurement ΔU (mv) a ) example 1 14 (-76) n = 7 Example 2 19 (-76) n = 3 a) the measured values from n tests are followed by the corresponding blank values in brackets. The blank values are the cell potentials when diazoxide is administered.

Claims (9)

Substituierte Benzolsulfonylharnstoffe und -thioharnstoffe I
Figure imgb0017
 worin bedeuten: R(1)   Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl; r   null, 1, 2, 3, 4 oder 5; p   1, 2, 3, 4, 5 oder 6; R(2)   NR(3)R(4), R(3) und R(4)   gemeinsam
eine (CH₂)₂₋₇-Kette, in der bei einer Kettenlänge von 4 bis 7 eine der CH₂-Gruppen durch Sauerstoff, Schwefel oder NR(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß;
oder R(3), R(4), R(5)   unabhängig voneinander
Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl; r   Null, 1, 2, 3, 4 oder 5; p   1, 2, 3, 4, 5 oder 6; E   Sauerstoff oder Schwefel; Y   eine Kohlenwasserstoffkette der Formel -[CR(6)₂]n-; R(6) Wasserstoff oder (C₁-C₂)-Alkyl; n   1, 2, 3 oder 4; X   Wasserstoff, F, Cl, Br, I oder (C₁-C₆)-Alkyl; Z   F, Cl, Br, I, NO₂, (C₁-C₄)-Alkoxy oder (C₁-C₄)-Alkyl. Substituted benzenesulfonylureas and thioureas I
Figure imgb0017
 in which mean: R (1) hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆) alkenyl; r zero, 1, 2, 3, 4 or 5; p 1, 2, 3, 4, 5 or 6; R (2) NR (3) R (4), R (3) and R (4) together
a (CH₂) ₂₋₇ chain in which one of the CH₂ groups with a chain length of 4 to 7 can be replaced by oxygen, sulfur or NR (5), wherein between the N atom of the NR (3) R ( 4) and the oxygen, sulfur or NR (5) must be at least one CH₂ group;
or R (3), R (4), R (5) independently of one another
Hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆ ) Alkenyl; r zero, 1, 2, 3, 4 or 5; p 1, 2, 3, 4, 5 or 6; E oxygen or sulfur; Y is a hydrocarbon chain of the formula - [CR (6) ₂] n -; R (6) is hydrogen or (C₁-C₂) alkyl; n 1, 2, 3 or 4; X is hydrogen, F, Cl, Br, I or (C₁-C₆) alkyl; Z F, Cl, Br, I, NO₂, (C₁-C₄) alkoxy or (C₁-C₄) alkyl. Verbindung der Formel I nach Anspruch 1, dadurch gekennzeichnet, daß darin bedeuten: R(1)   Wasserstoff, (C₁-C₄)-Alkyl, CpF2p+1, (C₃-C₅)-Cycloalkyl, CH₂-(C₃-C₅)-Cycloalkyl oder (C₃-C₄)-Alkenyl; p   1, 2 oder 3; R(2)   NR(3)R(4), R(3) und R(4)   gemeinsam
eine (CH₂)₂₋₇-Kette, in der bei einer Kettenlänge von 4 bis 7 eine der CH₂-Gruppen durch Sauerstoff, Schwefel oder NR(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß;
oder R(3), R(4), R(5)   unabhängig voneinander
Wasserstoff, (C₁-C₆)-Alkyl, (CH₂)r-CpF2p+1, (C₃-C₆)-Cycloalkyl, (C₁-C₂)-Alkyl-(C₃-C₅)-Cycloalkyl oder (C₂-C₆)-Alkenyl; r   Null, 1, 2, 3, 4 oder 5; p   1, 2, 3, 4, 5 oder 6; E   Sauerstoff oder Schwefel; Y   eine Kohlenwasserstoffkette der Formel -[R(6)₂]n-; R(6) Wasserstoff oder (C₁-C₂)-Alkyl; n 1, 2, 3 oder 4; X   Wasserstoff, F, Cl oder (C₁-C₄)-Alkyl; Z   Cl, F, (C₁-C₄)-Alkyl oder (C₁-C₄)-Alkoxy. Compound of formula I according to claim 1, characterized in that therein: R (1) hydrogen, (C₁-C₄) alkyl, C p F 2p + 1 , (C₃-C₅) cycloalkyl, CH₂- (C₃-C₅) cycloalkyl or (C₃-C₄) alkenyl; p 1, 2 or 3; R (2) NR (3) R (4), R (3) and R (4) together
a (CH₂) ₂₋₇ chain in which one of the CH₂ groups with a chain length of 4 to 7 can be replaced by oxygen, sulfur or NR (5), wherein between the N atom of the NR (3) R ( 4) and the oxygen, sulfur or NR (5) must be at least one CH₂ group;
or R (3), R (4), R (5) independently of one another
Hydrogen, (C₁-C₆) alkyl, (CH₂) r -C p F 2p + 1 , (C₃-C₆) cycloalkyl, (C₁-C₂) alkyl- (C₃-C₅) cycloalkyl or (C₂-C₆ ) Alkenyl; r zero, 1, 2, 3, 4 or 5; p 1, 2, 3, 4, 5 or 6; E oxygen or sulfur; Y is a hydrocarbon chain of the formula - [R (6) ₂] n -; R (6) is hydrogen or (C₁-C₂) alkyl; n 1, 2, 3 or 4; X is hydrogen, F, Cl or (C₁-C₄) alkyl; Z Cl, F, (C₁-C₄) alkyl or (C₁-C₄) alkoxy. Verbindung der Formel 1 nach Anspruch 1, dadurch gekennzeichnet, daß darin bedeuten: R(1)   Wasserstoff, (C₁-C₄)-Alkyl, (C₃-C₄)-Cycloalkyl oder (C₃-C₄)-Alkenyl; R(2)   NR(3)R(4), R(3) und R(4)   gemeinsam
eine (CH₂)₄₋₆ Kette, in der eine CH₂-Gruppe durch Sauerstoff, Schwefel oder N-R(5) ersetzt sein kann, wobei zwischen dem N-Atom des NR(3)R(4) und dem Sauerstoff, Schwefel oder NR(5) mindestens eine CH₂-Gruppe stehen muß, oder
oder R(3) und R(4)   unabhängig voneinander
CH₃, C₂H₅, n-Propyl, Iso-Propyl oder Cyclo-Propyl; R(5)   Wasserstoff, CH₃ oder C₂H₅; E   Sauerstoff oder Schwefel; Y   eine Kohlenwasserstoffkette der Formel -[CR(6)₂]n-; R(6) Wasserstoff oder Methyl; n   2 oder 3; X   Wasserstoff, Cl, F oder (C₁-C₃)-Alkyl; Z   F, Cl oder (C₁-C₃)-Alkoxy. Compound of formula 1 according to claim 1, characterized in that therein: R (1) hydrogen, (C₁-C₄) alkyl, (C₃-C₄) cycloalkyl or (C₃-C₄) alkenyl; R (2) NR (3) R (4), R (3) and R (4) together
a (CH₂) ₄₋₆ chain in which a CH₂ group can be replaced by oxygen, sulfur or NR (5), wherein between the N atom of the NR (3) R (4) and the oxygen, sulfur or NR (5) at least one CH₂ group, or
or R (3) and R (4) independently of one another
CH₃, C₂H₅, n-propyl, iso-propyl or cyclo-propyl; R (5) is hydrogen, CH₃ or C₂H₅; E oxygen or sulfur; Y is a hydrocarbon chain of the formula - [CR (6) ₂] n -; R (6) is hydrogen or methyl; n 2 or 3; X is hydrogen, Cl, F or (C₁-C₃) alkyl; Z F, Cl or (C₁-C₃) alkoxy. Verfahren zur Herstellung einer Verbindung I nach Anspruch 1, dadurch gekennzeichnet, daß man (a) aromatische Sulfonamide der Formel II oder deren Salze der Formel III
Figure imgb0018
 mit R(1)-substituierten Isocyanaten der Formel IV



        R(1) - N = C = O   IV



zu substituierten Benzolsulfonylharnstoffen I a umsetzt,
oder (b) einen unsubstituierten Benzolsulfonylharnstoff I a [R(1) = H]
Figure imgb0019
 durch Umsetzungen eines aromatischen Benzolsulfonamids der Formel II oder von dessen Salz III mit Trialkylsilylisocyanat oder Siliciumtetraisocyanat und Hydrolyse des primären siliciumsubstituierten Benzolsulfonylharnstoffs herstellt, oder (c) einen Benzolsulfonylharnstoff I a
Figure imgb0020
 aus einem aromatischen Benzolsulfonamid II oder dessen Salz III und R(1)-substituierten Trichloracetamiden der Formel V
Figure imgb0021
 in Gegenwart einer Base darstellt, oder (d) einen Benzolsulfonylthioharnstoff I b
Figure imgb0022
 aus einem Benzolsulfonamid II oder dessen Salz III und R(1)-substituierten Thioisocyanaten IV



        R(1) - N = C = S   IV



dargestellt, oder (e) einen Benzolsulfonylharnstoff I a durch Umsetzung eines Amins der Formel R(1)-NH₂ mit einem Benzolsulfonylisocyanat der Formel VII
Figure imgb0023
 herstellt, oder (f) einen Benzolsulfonylthioharnstoff I b durch Umsetzung eines Amins der Formel R(1)-NH₂ mit einem Benzolsulfonylisothiocyanat der Formel VIII
Figure imgb0024
 herstellt. A process for the preparation of a compound I according to claim 1, characterized in that (a) aromatic sulfonamides of the formula II or their salts of the formula III
Figure imgb0018
 with R (1) -substituted isocyanates of the formula IV



R (1) - N = C = O IV



converts to substituted benzenesulfonylureas I a,
or (b) an unsubstituted benzenesulfonylurea I a [R (1) = H]
Figure imgb0019
 by reacting an aromatic benzenesulfonamide of the formula II or its salt III with trialkylsilyl isocyanate or silicon tetraisocyanate and hydrolysis of the primary silicon-substituted benzenesulfonylurea, or (c) a benzenesulfonylurea I a
Figure imgb0020
 from an aromatic benzenesulfonamide II or its salt III and R (1) -substituted trichloroacetamides of the formula V
Figure imgb0021
 in the presence of a base, or (d) a benzenesulfonylthiourea I b
Figure imgb0022
 from a benzenesulfonamide II or its salt III and R (1) -substituted thioisocyanates IV



R (1) - N = C = S IV



illustrated or (e) a benzenesulfonylurea I a by reacting an amine of the formula R (1) -NH₂ with a benzenesulfonyl isocyanate of the formula VII
Figure imgb0023
 manufactures, or (f) a benzenesulfonylthiourea I b by reacting an amine of the formula R (1) -NH₂ with a benzenesulfonyl isothiocyanate of the formula VIII
Figure imgb0024
 manufactures. Verwendung einer Verbindung I nach Anspruch 1 zum Herstellen eines Medikaments zum Behandeln von Herzrhythmusstörungen.Use of a compound I according to claim 1 for the manufacture of a medicament for treating cardiac arrhythmias. Verwendung einer Verbindung I nach Anspruch 1 zum Herstellen eines cardioprotektiven Medikaments zur Prophylaxe des Infarkts und der angina pectoris.Use of a compound I according to claim 1 for the manufacture of a cardioprotective medicament for the prophylaxis of infarction and angina pectoris. Medikament, dadurch gekennzeichnet, daß es eine wirksame Menge einer Verbindung I nach Anspruch 1 enthält.Medicament, characterized in that it contains an effective amount of a compound I according to claim 1. Methode zum Behandeln von Arrhythmien, des Infarkts und zur Cardioprotektion, dadurch gekennzeichnet, daß man eine wirksame Menge einer Verbindung I nach Anspruch 1, die mit den üblichen Zusatzstoffen versetzt und in eine geeignete Darreichungsform gebracht ist, verabreicht.Method for treating arrhythmias, infarction and cardioprotection, characterized in that an effective amount of a compound I according to claim 1, which has been mixed with the usual additives and brought into a suitable dosage form, is administered. Verwendung einer Verbindung I nach Anspruch 1 zur Behandlung oder Prophylaxe von ischämischen Zuständen des Herzens.Use of a compound I according to claim 1 for the treatment or prophylaxis of ischemic conditions of the heart.
EP94118931A 1993-12-07 1994-12-01 Aminosubstituted benzoylsulfonylurea and thiourea derivatives, process for their preparation and their use as pharmaceuticals Expired - Lifetime EP0657423B1 (en)

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DE4341655A DE4341655A1 (en) 1993-12-07 1993-12-07 Amino-substituted benzenesulfonylureas and thioureas, processes for their preparation and their use as pharmaceuticals

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EP0657423A1 true EP0657423A1 (en) 1995-06-14
EP0657423B1 EP0657423B1 (en) 1998-12-30

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EP94118931A Expired - Lifetime EP0657423B1 (en) 1993-12-07 1994-12-01 Aminosubstituted benzoylsulfonylurea and thiourea derivatives, process for their preparation and their use as pharmaceuticals

Country Status (18)

Country Link
US (1) US5476850A (en)
EP (1) EP0657423B1 (en)
JP (1) JP3718246B2 (en)
KR (1) KR100338168B1 (en)
CN (1) CN1054372C (en)
AT (1) ATE175192T1 (en)
AU (1) AU678866B2 (en)
CA (1) CA2137441C (en)
DE (2) DE4341655A1 (en)
DK (1) DK0657423T3 (en)
ES (1) ES2127875T3 (en)
FI (1) FI107152B (en)
GR (1) GR3029768T3 (en)
HU (1) HU219228B (en)
IL (1) IL111870A (en)
NO (1) NO302468B1 (en)
NZ (1) NZ270062A (en)
ZA (1) ZA949687B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0729954A1 (en) * 1995-02-01 1996-09-04 Hoechst Aktiengesellschaft Substituted thiophene sulfonyl ureas and thioureas, process for their preparation, their use as medicaments
WO2000003978A2 (en) * 1998-07-16 2000-01-27 Aventis Pharma Deutschland Gmbh 2,5-substituted benzolsulfonylureas and thioureas, methods for the production thereof, use thereof and pharmaceutical preparations containing the same

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA961314B (en) * 1995-02-21 1996-08-27 Hoechst Ag Substituted benzenesulfonylureas and -thioreas processes for their preparation their use for the production of pharmaceutical preparations and medicaments containing them
US6503949B1 (en) 1999-05-17 2003-01-07 Noro Nordisk A/S Glucagon antagonists/inverse agonists
DE19923086A1 (en) 1999-05-20 2000-11-23 Aventis Pharma Gmbh New cinnamoylaminoalkyl-substituted benzenesulfonamide derivatives, are ATP-sensitive potassium channel inhibitors and vagal nervous system stimulants useful for treating cardiovascular disorders
DE10054482A1 (en) 2000-11-03 2002-05-08 Aventis Pharma Gmbh Heteroarylacryloylaminoalkyl-substituted benzenesulfonamide derivatives, their production, their use and pharmaceutical preparations containing them
DE10054481A1 (en) 2000-11-03 2002-05-08 Aventis Pharma Gmbh Acylaminoalkyl-substituted benzenesulfonamide derivatives, their preparation, their use and pharmaceutical compositions containing them
CN1330630C (en) * 2004-03-10 2007-08-08 中国药科大学 Sultonyl (thio)urea derivants, their preparation process and pharmaceutical composition containing them
DE102004061017A1 (en) * 2004-12-18 2006-06-22 Sanofi-Aventis Deutschland Gmbh Piperidinesulfonylureas and thioureas, their preparation, their use and pharmaceutical compositions containing them
WO2008148468A1 (en) * 2007-06-05 2008-12-11 Sanofi-Aventis Di(hetero)arylcyclohexane derivatives, their preparation, their use and pharmaceutical compositions comprising them
US20230348371A1 (en) * 2020-07-17 2023-11-02 Shanghai Senhui Medicine Co., Ltd. Sulfonylurea derivative and medical uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1518879A1 (en) * 1964-10-07 1969-08-14 Hoechst Ag Benzenesulfonylureas and process for their preparation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2413514C3 (en) * 1974-03-21 1982-03-04 Hoechst Ag, 6000 Frankfurt N-Acylaminoathylbenzenesulfonyl-N'-methylureas, process for their preparation and their use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1518879A1 (en) * 1964-10-07 1969-08-14 Hoechst Ag Benzenesulfonylureas and process for their preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
L. H. OPIE: "Modulation of ischemia by regulation of the ATP-sensitive potassium channel", CARDIOVASCULAR DRUGS AND THERAPY, vol. 7, 1 August 1993 (1993-08-01), pages 507-513 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0729954A1 (en) * 1995-02-01 1996-09-04 Hoechst Aktiengesellschaft Substituted thiophene sulfonyl ureas and thioureas, process for their preparation, their use as medicaments
US5792788A (en) * 1995-02-01 1998-08-11 Hoechst Aktiengesellschaft Substituted thiophenesulfonylureas and -thioureas, processes for their preparation, their use as a medicament or diagnostic, and medicament containing them
WO2000003978A2 (en) * 1998-07-16 2000-01-27 Aventis Pharma Deutschland Gmbh 2,5-substituted benzolsulfonylureas and thioureas, methods for the production thereof, use thereof and pharmaceutical preparations containing the same
WO2000003978A3 (en) * 1998-07-16 2000-09-14 Aventis Pharma Gmbh 2,5-substituted benzolsulfonylureas and thioureas, methods for the production thereof, use thereof and pharmaceutical preparations containing the same
US6410573B1 (en) 1998-07-16 2002-06-25 Aventis Pharma Deutschland Gmbh 2,5-substituted benzolsulfonylureas and thioureas methods for the production thereof use thereof and pharmaceutical preparations containing the same
CN1330632C (en) * 1998-07-16 2007-08-08 萨诺费－阿文蒂斯德国有限公司 2,5-substituted benzoluslfonylureas and thioureas, methods for production thereof, use thereof and pharamceutical preparations containing the same
CZ300828B6 (en) * 1998-07-16 2009-08-19 Sanofi - Aventis Deutschland GmbH 2,5-Substituted benzenesulfonyl ureas and -thioureas, process of their preparation, their use as well as pharmaceutical compositions in which they are comprised

Also Published As

Publication number Publication date
FI945729A (en) 1995-06-08
EP0657423B1 (en) 1998-12-30
FI945729A0 (en) 1994-12-05
CN1111238A (en) 1995-11-08
DE59407559D1 (en) 1999-02-11
HU9403486D0 (en) 1995-02-28
NO944699D0 (en) 1994-12-06
HU219228B (en) 2001-03-28
DE4341655A1 (en) 1995-06-08
CN1054372C (en) 2000-07-12
AU678866B2 (en) 1997-06-12
ES2127875T3 (en) 1999-05-01
KR950017942A (en) 1995-07-22
GR3029768T3 (en) 1999-06-30
JP3718246B2 (en) 2005-11-24
CA2137441A1 (en) 1995-06-08
ATE175192T1 (en) 1999-01-15
AU8021394A (en) 1995-06-15
HUT71125A (en) 1995-11-28
US5476850A (en) 1995-12-19
ZA949687B (en) 1995-07-10
CA2137441C (en) 2005-10-18
DK0657423T3 (en) 1999-07-19
FI107152B (en) 2001-06-15
NZ270062A (en) 1996-07-26
IL111870A0 (en) 1995-03-15
IL111870A (en) 1999-03-12
JPH07196597A (en) 1995-08-01
NO302468B1 (en) 1998-03-09
NO944699L (en) 1995-06-08
KR100338168B1 (en) 2003-02-11

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